The objectives of this proposal are to define the mechanisms of the secretion of lithogenic bile which underlie the increased incidence of cholesterol gallstones in women, especially during the child-bearing age and among those taking contraceptive steroids; to determine the effect of pregnancy, the normal ovulatory cycle and contraceptive steroids on @iliary lipids and bile acid kinetics, and to relate these effects to changes in naturally occurring female sex hormones: and to seek means of restoring biliary lipid secretion to normal and reducing cholesterol cholelithiasis in the above groups of patients. Mechanisms of estrogen effects will be studied by: (1) in vitro measurements of hepatic cholesterol 7 alpha-hydroxylase and cholesterol acyl CoA transferase activities and cholesterol ester concentrations in rats and hamsters treated with estrogens and in liver biopsy material from women at different ages, women taking contraceptive steroids and suitable controls, (2) in vivo measurements of the rate of bile acid synthesis in rats and hamsters during pregnancy and during treatment with estrogens and (3) measurements of the metabolic fate of labeled cholesterol and cholesterol substrates in isolated perfused livers of pregnant rats and rats treated with estrogens. Biliary lipid composition and bile acid kinetics will be measured in pregnant women, women during the normal ovulatory cycle, women receiving contraceptive steroids and in appropriate control groups. Bile-rich duodenal fluid will be used. For the kinetic studies, bile acids will be labeled with either the stable isotope, 13C, or the radioactive isotope, 14C, depending upon the study group. In all of these studies of patients, appropriate serum hormone concentrations will be determined and they will be correlated with changes in biliary lipids and bile acid kinetics. The capacity of phenobarbital and salicylates and possibly other agents to modify the estrogen effects will be tested in animals.